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Intravenous transferrin, RGD peptide and dual-targeted nanoparticles enhance anti-VEGF intraceptor gene delivery to laser-induced CNV

Gene Therapy volume 16, pages 645–659 (2009)Cite this article

Abstract

Choroidal neovascularization (CNV) leads to loss of vision in age-related macular degeneration (AMD), the leading cause of blindness in adult population over 50 years old. In this study, we developed intravenously administered, nanoparticulate, targeted nonviral retinal gene delivery systems for the management of CNV. CNV was induced in Brown Norway rats using a 532 nm laser. We engineered transferrin, arginine–glycine–aspartic acid (RGD) peptide or dual-functionalized poly-(lactide-co-glycolide) nanoparticles to target delivery of anti-vascular endothelial growth factor (VEGF) intraceptor plasmid to CNV lesions. Anti-VEGF intraceptor is the only intracellularly acting VEGF inhibitory modality. The results of the study show that nanoparticles allow targeted delivery to the neovascular eye but not the control eye on intravenous administration. Functionalizing the nanoparticle surface with transferrin, a linear RGD peptide or both increased the retinal delivery of nanoparticles and subsequently the intraceptor gene expression in retinal vascular endothelial cells, photoreceptor outer segments and retinal pigment epithelial cells when compared to nonfunctionalized nanoparticles. Most significantly, the CNV areas were significantly smaller in rats treated with functionalized nanoparticles as compared to the ones treated with vehicle or nonfunctionalized nanoparticles. Thus, surface-functionalized nanoparticles allow targeted gene delivery to the neovascular eye on intravenous administration and inhibit the progression of laser-induced CNV in a rodent model.

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Acknowledgements

This work was primarily supported by NIH grants R24 EY017045 and R21 EY017360. Creation of VEGF intraceptor plasmid by Dr BK Ambati was supported by NIH grant 5RO1EY017182. We thank James R Talaska and Janice Taylor of the Confocal Laser Scanning Microscopy Core Facility at University of Nebraska Medical Center, which is supported by the Nebraska Research Initiative, for providing assistance with confocal microscopy. We thank Karen Dulany and Maureen Harman of the Eppley Histology Core Laboratory at University of Nebraska Medical Center, for their help in cryosectioning of the tissues. We also thank Dr Chandrasekar Durairaj and Rajendra S Kadam for their assistance during the study. We especially thank Dr Weiqing Gao, Emory Eye Center, Emory university, Atlanta, GA, for assistance with choroidal flatmounts.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA

    S R Singh & U B Kompella

  2. Emory Eye Center, Emory University, Atlanta, GA, USA

    H E Grossniklaus, S J Kang & H F Edelhauser

  3. Moran Eye Institute, Salt Lake City, UT, USA

    B K Ambati

  4. Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA

    U B Kompella

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  1. S R Singh
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Correspondence to U B Kompella.

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Singh, S., Grossniklaus, H., Kang, S. et al. Intravenous transferrin, RGD peptide and dual-targeted nanoparticles enhance anti-VEGF intraceptor gene delivery to laser-induced CNV. Gene Ther 16, 645–659 (2009). https://doi.org/10.1038/gt.2008.185

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